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Diabetes mellitus (DM) affects 30% to 60% of patients with hereditary hemochromatosis (HH). The underlying pathophysiology of DM in patients with hemochromatosis has not been fully elucidated. We studied both insulin secretion and insulin sensitivity in a cohort of patients with HH. We studied glucose metabolism in 53 newly diagnosed HH patients using a standard 75-g oral glucose tolerance test. Basal and stimulated insulin sensitivities were calculated using the quantitative insulin sensitivity check index and oral glucose insulin sensitivity index, respectively. beta-Cell function was assessed using C-peptide concentrations during the oral glucose tolerance test after adjusting for ambient insulin sensitivity. Twenty healthy subjects served as the control group. Fifteen subjects (28%) with HH had abnormal glucose tolerance (AGT). Seven (13%) had DM, and 8 (15%) had impaired glucose tolerance. As well as higher fasting glucose and glycated hemoglobin, those with AGT had a higher fasting insulin and C-peptide levels compared with those with normal glucose tolerance (NGT) (all Ps < .05). Insulin sensitivity measurements showed that the subjects in HH group with AGT were more insulin resistant than the subjects with NGT and controls subjects (P < .05). No significant changes were observed between the groups with NGT and AGT regarding hepatic insulin extraction and both indices related to insulin release in subjects with HH. Our cohort of patients with hemochromatosis and AGT had features similar to typical type 2 DM patients. These findings challenge the traditional view that DM in hemochromatosis is due primarily to iron-induced beta-cell failure., ((c) 2010 Elsevier Inc. All rights reserved.)